Glucagon-Like Peptide 1 and Its Analogs Act in the Dorsal Raphe and Modulate Central Serotonin to Reduce Appetite and Body Weight

Abstract

Glucagon-like peptide 1 (GLP-1) and serotonin play critical roles in energy balance regulation. Both systems are exploited clinically as antiobesity strategies. Surprisingly, whether they interact in order to regulate energy balance is poorly understood. Here we investigated mechanisms by which GLP-1 and serotonin interact at the level of the central nervous system. Serotonin depletion impaired the ability of exendin-4, a clinically used GLP-1 analog, to reduce body weight in rats, suggesting that serotonin is a critical mediator of the energy balance impact of GLP-1 receptor (GLP-1R) activation. Serotonin turnover and expression of 5-hydroxytryptamine (5-HT) 2A (5-HT) and 5-HT serotonin receptors in the hypothalamus were altered by GLP-1R activation. We demonstrate that the 5-HT, but surprisingly not the 5-HT, receptor is critical for weight loss, anorexia, and fat mass reduction induced by central GLP-1R activation. Importantly, central 5-HT receptors are also required for peripherally injected liraglutide to reduce feeding and weight. Dorsal raphe (DR) harbors cell bodies of serotonin-producing neurons that supply serotonin to the hypothalamic nuclei. We show that GLP-1R stimulation in DR is sufficient to induce hypophagia and increase the electrical activity of the DR serotonin neurons. Finally, our results disassociate brain metabolic and emotionality pathways impacted by GLP-1R activation. This study identifies serotonin as a new critical neural substrate for GLP-1 impact on energy homeostasis and expands the current map of brain areas impacted by GLP-1R activation.

Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) in the Brain–Adipocyte Axis

“…Anderberg et al [32] demonstrated that long-term stimulation with GLP-1RAs promoted an increase in the expression of serotonergic receptors in the hypothalamus. In addition, they showed that the 5-hydroxytryptamine 2A (5-HT 2A ) receptor is crucial for GLP-1RA-induced weight loss after exendin-4 ICV injection, such as peripheral injection of liraglutide in rats.…”

Anti-Obesity Therapy: from Rainbow Pills to Polyagonists

“…Supporting the notion that the brain plays a seminal role in glycemic control, coadministration of Lorcaserin with metformin or sulfonylureas potentiates the ability of the antidiabetic agents to improve HbA1c and fasting glucose levels in obese subjects with T2D (Moore, 1990). Preclinical studies have explored the prospect of combinatorial targeting of 5-HT2A/C receptors and GLP-1RAs (Anderberg et al, 2017), and it appears that the benefits of Lorcaserin can be increased in combinatorial settings.…”

Psychopharmacological advances in eating disorders

“…An important orexigenic signal leading to hunger and food intake is ghrelin which is produced in the stomach [77]. Anorexigenic signals from the body periphery include glucose, the enterocyte hormone glucagon-like peptide-1 (GLP-1) [78], the pancreatic hormone insulin and the fatty tissue hormone leptin [76]. In the hypothalamus, the arcuate nucleus, the paraventricular nucleus and the lateral hypothalamus are of particular relevance for weight regulation [76,79].…”